Novel tricyclic dihydropyrimidine compounds and their derivatives can open potassium channels and are useful for treating a variety of medical conditions.
Potassium channels play an important role in regulating cell membrane excitability. When the potassium channels open, changes in the electrical potential across the cell membrane occur and result in a more polarized state. A number of diseases or conditions may be treated with therapeutic agents that open potassium channels; for example, see K. Lawson, Pharmacol. Ther., v. 70, pp. 39-63 (1996); D. R. Gehlert et al., Prog. Neuro-Psychopharmacol and Biol. Psychiat., v. 18, pp. 1093-1102 (1994); M. Gopalakrishnan et al., Drug Development Research, v. 28, pp. 95-127 (1993); J. E. Freedman et al., The Neuroscientist, v. 2, pp. 145-152 (1996); D. E. Nurse et al., Br. J. Urol., v. 68 pp. 27-31 (1991); B. B. Howe et al., J. Pharmacol. Exp. Ther., v. 274 pp. 884-890 (1995); D. Spanswick et al., Nature, v. 390 pp. 521-25 (Dec. 4, 1997); Dompeling Vasa. Supplementum (1992) 3434; WO9932495; Grover, J Mol Cell Cardiol. (2000) 32, 677; and Buchheit, Pulmonary Pharmacology and Therapeutics (1999) 12, 103. Such diseases or conditions include asthma, hypertension, epilepsy, male sexual dysfunction, female sexual dysfunction, pain, bladder overactivity, stroke, diseases associated with decreased skeletal blood flow such as Raynaud""s phenomenon and intermittent claudication, eating disorders, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, coronary artery disease, angina and ischemia.
Bladder overactivity is a condition associated with the spontaneous, uncontrolled contractions of the bladder smooth muscle. Bladder overactivity thus is associated with or can cause diseases and/or conditions such as sensations of urgency, urinary incontinence, pollakiuria, bladder instability, nocturia, bladder hyerreflexia, and enuresis (Resnick, The Lancet (1995) 346, 94-99; Hampel, Urology (1997) 50 (Suppl 6A), 4-14; Bosch, BJU International (1999) 83 (Suppl 2), 7-9). Potassium channel openers (KCOs) act as smooth muscle relaxants. Because bladder overactivity and urinary incontinence can result from the spontaneous, uncontrolled contractions of the smooth muscle of the bladder, the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, urinary incontinence, and enuresis (Andersson, Urology (1997) 50 (Suppl 6A), 74-84; Lawson, Pharmacol. Ther., (1996) 70, 39-63; Nurse., Br. J. Urol., (1991) 68, 27-31; Howe, J. Pharmacol. Exp. Ther., (1995) 274, 884-890; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
The irritative symptoms of BPH (urgency, frequency, nocturia and urge incontinence) have been shown to be correlated to bladder instability (Pandita, The J. of Urology (1999) 162, 943). Therefore the ability of potassium channel openers to hyperpolarize bladder cells and relax bladder smooth muscle may provide a method to ameliorate or prevent the symptoms of BPH. (Andersson; Prostate (1997) 30: 202-215).
The excitability of corpus cavemosum smooth muscle cells is important in the male erectile process. The relaxation of corporal smooth muscle cells allows arterial blood to build up under pressure in the erectile tissue of the penis leading to erection (Andersson, Pharmacological Reviews (1993) 45, 253). Potassium channels play a significant role in modulating human corporal smooth muscle tone, and thus, erectile capacity. By patch clamp technique, potassium channels have been characterized in human corporal smooth muscle cells (Lee, Int. J. Impot. Res. (1999) 11(4),179-188). Potassium channel openers are smooth muscle relaxants and have been shown to relax corpus cavemosal smooth muscle and induce erections (Andersson, Pharmacological Reviews (1993) 45, 253; Lawson, Pharmacol. Ther., (1996) 70, 39-63, Vick, J. Urol. (2000) 163: 202). Potassium channel openers therefore may have utility in the treatment of male sexual dysfunctions such as male erectile dysfunction, impotence and premature ejaculation.
The sexual response in women is classified into four stages: excitement, plateau, orgasm and resolution. Sexual arousal and excitement increase blood flow to the genital area, and lubrication of the vagina as a result of plasma transudation. Topical application of KCOs like minoxidil and nicorandil have been shown to increase clitoral blood flow (J. J. Kim, J. W. Yu, J. G. Lee, D. G. Moon, xe2x80x9cEffects of topical K-ATP channel opener solution on clitoral blood flowxe2x80x9d, J. Urol. (2000) 163 (4): 240). KCOs may be effective for the treatment of female sexual dysfunction including clitoral erectile insufficiency, vaginismus and vaginal engorgement (I. Goldstein and J. R. Berman., xe2x80x9cVasculogenic female sexual dysfunction: vaginal engorgement and clitoral erectile insufficiency syndromesxe2x80x9d., Int. J. Impotence Res. (1998) 10:S84-S90), as KCOs can increase blood flow to female sexual organs.
Potassium channel openers may have utility as tocolytic agents to inhibit uterine contractions to delay or prevent premature parturition in individuals or to slow or arrest delivery for brief periods to undertake other therapeutic measures (Sanborn, Semin. Perinatol. (1995) 19, 31-40; Morrison, Am. J. Obstet. Gynecol. (1993) 169(5), 1277-85). Potassium channel openers also inhibit contractile responses of human uterus and intrauterine vasculature. This combined effect would suggest the potential use of KCOs for dysmenhorrea (Kostrzewska, Acta Obstet. Gynecol. Scand. (1996) 75(10), 886-91). Potassium channel openers relax uterine smooth muscle and intrauterine vasculature and therefore may have utility in the treatment of premature labor and dysmenorrhoea (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
Potassium channel openers relax gastrointestinal smooth tissues and therefore may be useful in the treatment of functional bowel disorders such as irritable bowel syndrome (Lawson, Pharmacol. Ther., (1996) 70, 39-63).
Potassium channel openers relax airways smooth muscle and induce bronchodilation. Therefore potassium channel openers may be useful in the treatment of asthma and airways hyperreactivity (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Buchheit, Pulmonary Pharmacology and Therapeutics (1999) 12, 103; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
Neuronal hyperpolarization can produce analgesic effects. The opening of potassium channels by potassium channel openers and resultant hyperpolarization in the membrane of target neurons is a key mechanism in the effect of opioids. The peripheral antinociceptive effect of morphine results from activation of ATP-sensitive potassium channels, which causes hyperpolarization of peripheral terminals of primary afferents, leading to a decrease in action potential generation (Rodrigues, Br J Pharmacol (2000) 129(1), 110-4). Opening of KATP channels by potassium channel openers plays an important role in the antinociception mediated by alpha-2 adrenoceptors and mu opioid receptors. KCOs can potentiate the analgesic action of both morphine and dexmedetomidine via an activation of KATP channels at the spinal cord level (Vergoni, Life Sci. (1992) 50(16), PL135-8; Asano, Anesth. Analg. (2000) 90(5), 1146-51). Thus, potassium channel openers can hyperpolarize neuronal cells and have shown analgesic effects. Potassium channel openers therefore may be useful as analgesics in the treatment of various pain states including but not limited to migraine and dyspareunia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., (1994) 18, 1093-1102).
Epilepsy results from the propagation of nonphysiologic electrical impulses. Potassium channel openers hyperpolarize neuronal cells and lead to a decrease in cellular excitability and have demonstrated antiepileptic effects. Therefore potassium channel openers may be useful in the treatment of epilepsy (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol. and Biol. Psychiat., (1994) 18, 1093-1102).
Neuronal cell depolarization can lead to excitotoxicity and neuronal cell death. When this occurs as a result of acute ischemic conditions, it can lead to stroke. Long-term neurodegeneration can bring about conditions such as Alzheimer""s and Parkinson""s diseases. Potassium channel openers can hyperpolarize neuronal cells and lead to a decrease in cellular excitability. Activation of potassium channels has been shown to enhance neuronal survival. Therefore potassium channel openers may have utility as neuroprotectants in the treatment of neurodegenerative conditions and diseases such as cerebral ischemia, stroke, Alzheimer""s disease and Parkinson""s disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Gehlert, Prog. Neuro-Psychopharmacol and Biol. Psychiat., (1994) 18, 1093-1102; Freedman, The Neuroscientist (1996) 2, 145).
Potassium channel openers may have utility in the treatment of diseases or conditions associated with decreased skeletal muscle blood flow such as Raynaud""s syndrome and intermittent claudication (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127; Dompeling Vasa. Supplementum (1992) 3434; and WO9932495).
Potassium channel openers may be useful in the treatment of eating disorders such as obesity (Spanswick, Nature, (1997) 390, 521-25; Freedman, The Neuroscientist (1996) 2, 145).
Potassium channel openers have been shown to promote hair growth therefore potassium channel openers have utility in the treatment of hair loss and baldness also known as alopecia (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
Potassium channel openers possess cardioprotective effects against myocardial injury during ischemia and reperfusion. (Garlid, Circ. Res. (1997) 81(6), 1072-82). Therefore, potassium channel openers may be useful in the treatment of heart diseases (Lawson, Pharmacol. Ther., (1996) 70, 39-63; Grover, J. Mol. Cell Cardiol. (2000) 32, 677).
Potassium channel openers, by hyperpolarization of smooth muscle membranes, can exert vasodilation of the collateral circulation of the coronary vasculature leading to increase blood flow to ischemic areas and could be useful for the coronary artery disease (Lawson, Pharmacol. Ther., (1996) 70, 39-63, Gopalakrishnan, Drug Development Research, (1993) 28, 95-127).
U.S. Pat. No. 4,918,074, EP 183848 B1, EP 217142, EP 328700, JP 63060985, JP 63243029, JP 61227584, and Atwal, K. S., Bioorg. Med. Chem. Lett (1991) 1, 291-294 disclose bicyclic 4,7-dihydropyrazolo[1,5-a]pyrimidines.
The compounds of the present invention are novel and hyperpolarize cell membranes, open potassium channels and relax smooth muscle cells.
In its principle embodiment, the present invention discloses compounds of formula (I): 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein,
n is an integer of 0-1;
m is an integer of 1-2;
provided that when m is 2, n is 0;
R1 is selected from aryl and heterocycle;
Q is selected from C(O), S(O), and S(O)2;
V is selected from C(R6)(R7), O, S, and NR2, wherein R2 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl;
R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above;
R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above;
X is selected from N and CR3 wherein R3 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above; and
D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above.
All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.
In its principle embodiment, the present invention discloses compounds of formula (I): 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein,
n is an integer of 0-1;
m is an integer of 1-2;
provided that when m is 2, n is 0;
R1 is selected from aryl and heterocycle;
Q is selected from C(O), S(O), and S(O)2;
V is selected from C(R6)(R7), O, S, and NR2, wherein R2 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl;
R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above;
R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above;
X is selected from N and CR3 wherein R3 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above; and
D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above.
In another embodiment of the present invention, compounds have formula (I) wherein, R1 is aryl; X is CR3; R3 is hydrogen; and R8, R9, D, E, Q, V, m, and n are as defined in formula (I).
In another embodiment of the present invention, compounds have formula (I) wherein, R1 is heterocycle; X is CR3; R3 is hydrogen; and R8, R9, D, E, Q, V, m, and n are as defined in formula (I).
In a preferred embodiment, compounds of the present invention have formula (II): 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein,
R1 is selected from aryl and heterocycle;
Q is selected from C(O), S(O), and S(O)2;
V is selected from C(R6)(R7), O, S, and NR2, wherein R2 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl;
R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above;
R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above; and
D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is C(O); and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is S(O); and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is S(O)2; and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is C(O); V is S; and R8, R9, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is C(O); V is S; and R8, R9, D, and E are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is C(O); V is CH2; and R8, R9, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is C(O); V is CH2; E is alkyl; D is alkyl; and R8 and R9 are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is C(O); V is CH2; E is alkyl; D is alkyl; and R8 and R9 are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is C(O); V is CH2; and R8, R9, D, and E are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is S(O)2; V is CH2; and R8, R9, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is heterocycle; Q is S(O)2; V is CH2; and R8, R9, D, and E are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is S; and R8, R9, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is S; and R8, R9, D, and E are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; and R8, R9, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; D is alkyl; E is alkyl; and R8 and R9 are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; D is alkyl; E is alkyl; and R8 and R9 are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; R9 is aryl; and R8, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; R9 is aryl; and R8, D, and E are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; R9 is heterocycle; and R8, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; R9 is heterocycle; and R8, D, and E are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; R9 is halogen; and R8, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; R9 is halogen; and R8, D, and E are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is C(O); V is CH2; and R8, R9, D, and E are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is S(O); and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is S(O)2; and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is S(O)2; V is CH2; and R8, R9, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (II) wherein, R1 is aryl; Q is S(O)2; V is CH2; and R8, R9, D, and E are hydrogen.
In another preferred embodiment, compounds of the present invention have formula (III): 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein,
R1 is selected from aryl and heterocycle;
Q is selected from C(O), S(O), and S(O)2;
V is selected from C(R6)(R7), O, S, and NR2, wherein R2 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl;
R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above;
R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above; and
D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above.
In another preferred embodiment of the present invention, compounds have formula (III) wherein, R1 is heterocycle; Q is C(O); and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (III) wherein, R1 is heterocycle; Q is S(O); and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (III) wherein, R1 is heterocycle; Q is S(O)2; and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (III) wherein, R1 is aryl; Q is C(O); and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (III) wherein, R1 is aryl; Q is C(O); V is O; and R8, R9, D, and E are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (III) wherein, R1 is aryl; Q is C(O); V is O; and R8, R9, D, and E are hydrogen.
In another preferred embodiment of the present invention, compounds have formula (III) wherein, R1 is aryl; Q is S(O); and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment of the present invention, compounds have formula (III) wherein, R1 is aryl; Q is S(O)2; and R8, R9, D, E, and V are as defined in formula (I).
In another preferred embodiment, compounds of the present invention have formula (IV): 
or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof wherein,
R1 is selected from aryl and heterocycle;
Q is selected from C(O), S(O), and S(O)2;
V is selected from C(R6)(R7), O, S, and NR2, wherein R2 is selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are independently selected from hydrogen and lower alkyl;
R6 and R7 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above;
R8 and R9 are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above; and
D and E are independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylthio, alkynyl, aryl, arylalkoxy, arylalkenyl, arylalkyl, carboxy, cyano, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, hydroxy, hydroxyalkyl, oxo, xe2x80x94NR4R5, and (NR4R5)alkyl wherein R4 and R5 are as defined above.
In another preferred embodiment of the present invention, compounds have formula (IV) wherein, R1 is heterocycle; Q is C(O); R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV).
In another preferred embodiment of the present invention, compounds have formula (IV) wherein, R1 is heterocycle; Q is S(O); R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV).
In another preferred embodiment of the present invention, compounds have formula (IV) wherein, R1 is heterocycle; Q is S(O)2; R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV).
In another preferred embodiment of the present invention, compounds have formula (IV) wherein, R1 is aryl; Q is C(O); R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV).
In another preferred embodiment of the present invention, compounds have formula (IV) wherein, R1 is aryl; Q is S(O); R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV).
In another preferred embodiment of the present invention, compounds have formula (IV) wherein, R1 is aryl; Q is S(O)2; R8, R9, D, and E are as defined in formula (I); and V is as defined in formula (IV).
Another embodiment of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I-IV) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof in combination with a pharmaceutically acceptable carrier.
Another embodiment of the invention relates to a method of treating male sexual dysfunction including, but not limited to, male erectile dysfunction and premature ejaculation, comprising administering a therapeutically effective amount of a compound of formula (I-IV) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Another embodiment of the invention relates to a method of treating female sexual dysfunction including, but not limited to, female anorgasmia, clitoral erectile insufficiency, vaginal engorgement, dyspareunia, and vaginismus comprising administering a therapeutically effective amount of a compound of formula (I-IV) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
Yet another embodiment of the invention relates to a method of treating asthma, epilepsy, Raynaud""s syndrome, intermittent claudication, migraine, pain, bladder overactivity, pollakiuria, bladder instability, nocturia, bladder hyperreflexia, eating disorders, urinary incontinence, enuresis, functional bowel disorders, neurodegeneration, benign prostatic hyperplasia (BPH), dysmenorrhea, premature labor, alopecia, cardioprotection, and ischemia comprising administering a therapeutically effective amount of a compound of formula (I-IV) or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
As used throughout this specification and the appended claims, the following terms have the following meanings.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of xe2x80x9calkenylxe2x80x9d include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl and the like.
The term xe2x80x9calkenyloxy,xe2x80x9d as used herein, refers to an alkenyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkenyloxy include, but are not limited to, propen-3-yloxy (allyloxy), buten-4-yloxy, and the like.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
The term xe2x80x9calkoxyalkoxy,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through another alkoxy group, as defined herein. Representative examples of alkoxyalkoxy include, but are not limited to, tert-butoxymethoxy, 2-ethoxyethoxy, 2-methoxyethoxy, methoxymethoxy, and the like.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, and the like.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.
The term xe2x80x9calkylcarbonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, 1-oxopentyl, and the like.
The term xe2x80x9calkylcarbonyloxy,xe2x80x9d as used herein, refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, tert-butylcarbonyloxy, and the like.
The term xe2x80x9calkylsulfinyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein. Representative examples of alkylsulfinyl include, but are not limited, methylsulfinyl, ethylsulfinyl, and the like.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited, methylsulfonyl, ethylsulfonyl, and the like.
The term xe2x80x9calkylthio,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like.
The aryl groups of this invention can be substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, aryloxy, azido, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, sulfamyl, sulfo, sulfonate, xe2x80x94NR80R81 (wherein, R80 and R81 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and xe2x80x94C(O)NR82R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl).
The term xe2x80x9carylalkenyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkenyl group, as defined herein. Representative examples of arylalkenyl include, but are not limited to, 2-phenylethenyl, 3-phenylpropen-2-yl, 2-naphth-2-ylethenyl, and the like.
The term xe2x80x9carylalkoxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy, 5-phenylpentyloxy, and the like.
The term xe2x80x9carylalkoxycarbonyl,xe2x80x9d as used herein, refers to an arylalkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylalkoxy include, but are not limited to, benzyloxycarbonyl, naphth-2-ylmethoxycarbonyl, and the like.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. Representative examples of aryloxy include, but are not limited to, phenoxy, naphthyloxy, and the like.
The term xe2x80x9cazido,xe2x80x9d as used herein, refers to an xe2x80x94N3 group.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to a xe2x80x94CO2H group.
The term xe2x80x9ccarboxy protecting group,xe2x80x9d as used herein, refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy-protecting groups are disclosed in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley and Sons, New York (1991), which is hereby incorporated herein by reference. In addition, a carboxy-protecting group can be used as a prodrug whereby the carboxy-protecting group can be readily cleaved in vivo, for example by enzymatic hydrolysis, to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in xe2x80x9cPro-drugs as Novel Delivery Systemsxe2x80x9d, Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy-protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference. Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of xe2x80x9cBioreversible Carriers in Drug Design: Theory and Applicationxe2x80x9d, edited by E. B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference. Representative carboxy-protecting groups are loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); benzyl (phenylmethyl) and substituted benzyl derivatives thereof such substituents are selected from alkoxy, alkyl, halogen, and nitro groups and the like.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to a xe2x80x94CN group.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons. Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl, and the like.
The term xe2x80x9cformyl,xe2x80x9d as used herein, refers to a xe2x80x94C(O)H group.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d as used herein, refers to xe2x80x94Cl, xe2x80x94Br, xe2x80x94I or xe2x80x94F.
The term xe2x80x9chaloalkyl,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
The term xe2x80x9chaloalkoxy,xe2x80x9d as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of haloalkoxy include, but are not limited to, 2-chloroethoxy, difluoromethoxy, 1,2-difluoroethoxy, 2,2,2-trifluoroethoxy, trifluoromethoxy, and the like.
The term xe2x80x9cheterocycle,xe2x80x9d as used herein, refers to a monocyclic- or a bicyclic-ring system. Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like.
The heterocycle groups of this invention can be substituted with 1, 2,or 3 substituents independently selected from alkenyl, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, aryl, azido, arylalkoxy, arylalkoxycarbonyl, arylalkyl, aryloxy, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, mercapto, nitro, sulfamyl, sulfo, sulfonate, xe2x80x94NR80R81 (wherein, R80 and R81 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl and formyl), and xe2x80x94C(O)NR82R83 (wherein, R82 and R83 are independently selected from hydrogen, alkyl, aryl, and arylalkyl).
The term xe2x80x9cheterocycle,xe2x80x9d as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyrid-3-ylmethyl, 2-pyrimidin-2-ylpropyl, and the like.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to an xe2x80x94OH group.
The term xe2x80x9chydroxyalkyl,xe2x80x9d as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like.
The term xe2x80x9clower alkyl,xe2x80x9d as used herein, is a subset of alkyl as defined herein and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like.
The term xe2x80x9cmercapto,xe2x80x9d as used herein, refers to a xe2x80x94SH group.
The term xe2x80x9c(NR4R5)alkyl,xe2x80x9d as used herein, refers to a xe2x80x94NR4R5 group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of (NR4R5)alkyl include, but are not limited to, aminomethyl, dimethylaminomethyl, 2-(amino)ethyl, 2-(dimethylamino)ethyl, and the like.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to a xe2x80x94NO2 group.
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to a xe2x95x90O moiety.
The term xe2x80x9coxy,xe2x80x9d as used herein, refers to a xe2x80x94Oxe2x80x94 moiety.
The term xe2x80x9csulfamyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2NR94R95 group, wherein, R94 and R95 are independently selected from hydrogen, alkyl, aryl, and arylalkyl, as defined herein.
The term xe2x80x9csulfinyl,xe2x80x9d as used herein, refers to a xe2x80x94S(O)xe2x80x94 group.
The term xe2x80x9csulfo,xe2x80x9d as used herein, refers to a xe2x80x94SO3H group.
The term xe2x80x9csulfonate,xe2x80x9d as used herein, refers to a xe2x80x94S(O)2OR96 group, wherein, R96 is selected from alkyl, aryl, and arylalkyl, as defined herein.
The term xe2x80x9csulfonyl,xe2x80x9d as used herein, refers to a xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9cthio,xe2x80x9d as used herein, refers to a xe2x80x94Sxe2x80x94 moiety.
Preferred compounds of formula (I) include, but are not limited to:
9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-bromo-4-fluorophenyl)-5,9-dihydro-4H-pyrazolo[1,5-a]thiopyrano[3,4-d]pyrimidin-8(7H)-one;
9-(1-naphthyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(2-naphthyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dibromophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dichlorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-bromophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-chlorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-[4-chloro-3-(trifluoromethyl)phenyl]-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-[4-fluoro-3-(trifluoromethyl)phenyl]-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-[3-(trifluoromethoxy)phenyl]-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-cyanophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-methylphenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
8-(3-bromo-4-fluorophenyl)-5,8-dihydro-4H,7H-furo[3,4-d]pyrazolo[1,5-a]pyrimidin-7-one;
(xe2x88x92) 9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
(+) 9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydro-4H-pyrazolo[1,5-a]thiopyrano[3,2-d]pyrimidine 8,8-dioxide,
9-(3-chloro-4-hydroxyphenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
3-bromo-9-(3-bromo-4-fluorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-chloro-4-fluorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-difluorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(4-fluorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-[4-(trifluoromethyl)phenyl]-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(4-cyanophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(4-chloro-3-nitrophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(4-chloro-3-fluorophenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-bromo-4-fluorophenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-[4-fluoro-3-(trifluoromethyl)phenyl]-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dichlorophenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(4-chloro-3-nitrophenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dibromophenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-[3-fluoro-4-(trifluoromethyl)phenyl]-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-nitrophenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-cyanophenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
7,7-dimethyl-9-(5-nitro-3-thienyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(5-bromo-2-hydroxyphenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(5-chloro-2-hydroxyphenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(2-hydroxy-5-nitrophenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,5-dibromo-2-hydroxyphenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3-bromo-5-chloro-2-hydroxyphenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,5-dichloro-2-hydroxyphenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4,5-trifluorophenyl)-7,7-dimethyl-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dichlorophenyl)-3-(3-fluorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dichlorophenyl)-3-(3-chlorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dichlorophenyl)-3-(4-carboxyphenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dichloropbenyl)-3-(2-thienyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dichlorophenyl)-3-[2-(trifluoromethyl)phenyl]-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
3-bromo-9-(3,4-dichlorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
(+) 3-bromo-9-(3,4-dichlorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
(xe2x88x92) 3-bromo-9-(3,4-dichlorophenyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
(+) 9-(3,4-dichlorophenyl)-3-(2-thienyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
(xe2x88x92) 9-(3,4-dichlorophenyl)-3-(2-thienyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one;
9-(3,4-dichlorophenyl)-3-(2-furyl)-5,6,7,9-tetrahydropyrazolo[5,1-b]quinazolin-8(4H)-one and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds of the invention can be prepared.
The compounds of this invention can be prepared by a variety of synthetic routes. Representative procedures are shown in Schemes 1-20. 
Fused pyrimidines of general formula (4), wherein R1, X, Q, R8, R9, D and E are as defined in formula (I) and m is an integer 1-2, can be prepared according to the method of Scheme 1. A carbonyl component of general formula (1) can be treated with an aldehyde of general formula (2) and an amino heterocycle of general formula (3) in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide fused pyrimidines of general formula (4). 
Fused pyrimidines of general formula (6), wherein R1, X, Q, V, R8, R9, D, and E are as defined in formula (I), can be prepared according to the method of Scheme 2. A carbonyl component of general formula (5) can be treated with an aldehyde of general formula (2) and an amino heterocycle of general formula (3) in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide fused pyrimidines of general formula (6). Carbonyl components of general formula (5) may be prepared using the procedures described in (Dodd, J. H., Journal of Heterocyclic Chemistry 27 (1990) 1453; Terasawa, T., Journal of Organic Chemistry 42 (1977) 1163). 
Fused pyrimidines of general formula (8), wherein R1, X, Q, V, R8, R9, D, and E are as defined in formula (I), can be prepared according to the method of Scheme 3. A carbonyl component of general formula (7) can be treated with an aldehyde of general formula (2) and an amino heterocycle of general formula (3) in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide fused pyrimidines of general formula (8). Carbonyl components of general formula (7) may be prepared as described in (Nakagawa, S., Heterocycles 13 (1979) 477; D""Angelo, J., Tetrahedron Letters 32 (1991) 3063). 
Fused pyrimidines of general formula (10), wherein R1, X, Q, V, R8, R9, D, and E are as defined in formula (I), can be prepared according to the method of Scheme 4. A carbonyl component of general formula (9) can be treated with an aldehyde of general formula (2) and an amino heterocycle of general formula (3) in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide fused pyrimidines of general formula (10). 
Fused pyrimidines of general formula (13), wherein R1, X, R8, R9, and D are as defined in formula (I), can be prepared according to the method of Scheme 5. A dicarbonyl component of general formula (11), wherein R1 is selected from Cl and OAc and R is selected from lower alkyl, cyanoalkyl, and carboxy protecting group, can be treated with an aldehyde of general formula (2) and an amino heterocycle of general formula (3) in a solvent such as ethanol, acetonitrile or dimethylformamide with heating to provide fused pyrimidines of general formula (12). In the case where Rxe2x80x2 is OAc, cleavage of the acetyl group may be required to induce cyclization to provide fused pyrimidines of general formula (13). In the case where Rxe2x80x2 is Cl, cyclization can proceed directly without the isolation of (12) to provide fused pyrimidines of general formula (13).
Many of the starting aryl and heteroaryl aldehydes necessary to carry out the methods described in the preceeding and following Schemes may be purchased from commercial sources or may be synthesized by known procedures found in the chemical literature. Appropriate literature references for the preparation of aryl and heteroaryl aldehydes may be found in the following section or in the Examples. For starting materials not previously described in the literature the following Schemes are intended to illustrate their preparation through a general method.
The preparation of aldehydes used to synthesize many preferred compounds of the invention may be found in the following literature references: Pearson, Org. Synth. Coll. Vol V (1973), 117; Nwaukwa, Tetrahedron Lett. (1982), 23, 3131; Badder, J. Indian Chem. Soc. (1976), 53, 1053; Khanna, J. Med. Chem. (1997), 40, 1634; Rinkes, Recl. Trav. Chim. Pays-Bas (1945), 64, 205; van der Lee, Recl. Trav. Chim. Pays-Bas (1926), 45, 687; Widman, Chem. Ber. (1882), 15,167; Hodgson, J. Chem. Soc. (1927), 2425; Clark, J. Fluorine Chem. (1990), 50, 411; Hodgson, J. Chem. Soc. (1929), 1635; Duff, J. Chem. Soc. (1951), 1512; Crawford, J. Chem. Soc. (1956), 2155; Tanouchi, J. Med. Chem. (1981), 24, 1149; Bergmann, J. Am. Chem. Soc. (1959), 81,5641; Other: Eistert, Chem. Ber. (1964), 97, 1470; Sekikawa, Bull. Chem. Soc. Jpn. (1959), 32, 551. 
Meta, para-disubstituted aldehydes of general formula (21), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, xe2x80x94NR82R83, and xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halo, and alkylcarbonyl, can be prepared according to the method described in Scheme 6. A para substituted aldehyde of general formula (20) or the corresponding acetal protected aldehyde of general formula (22), wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, may by subjected to conditions of an electrophilic aromatic substitution reaction to provide aldehydes of general formula (21) or protected aldehydes of general formula (23). Preferred protecting groups for compounds of general formula (22) and (23) include dimethyl or diethyl acetals or the 1,3-dioxolanes. These protecting groups can be introduced at the beginning and removed at the end to provide substituted aldehydes of general formula (21) using methods well known to those skilled in the art of organic chemistry. 
Aldehydes of general formula (27), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, xe2x80x94NR82R83, and xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halo, and alkylcarbonyl, can be prepared by the method described in Scheme 7. A meta substituted phenol (25) is converted to the para substituted salicylaldehyde (26) by reaction with a base such as sodium hydroxide and a reagent such as trichloromethane or tribromomethane, known as the Reimer-Tiemann reaction. An alternate set of reaction conditions involves reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). The aldehyde (26) may be subjected to conditions of an electrophilic aromatic substitution reaction to provide meta, para disubstituted salicylaldehydes of general formula (27). 
An alternative method of preparing meta, para disubstituted salicylaldehydes of general formula (27), wherein R10 is selected from alkyl, haloalkyl, halo, haloalkoxy, alkoxy, alkylthio, xe2x80x94NR82R83, and xe2x80x94C(O)NR82R83, wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl and R12 is selected from nitro, halo, and alkylcarbonyl, can be used as described in Scheme 8. A meta, para disubstituted phenol of general formula (28) can be reacted with a base such as sodium hydroxide and a reagent such as trichloromethane or tribromomethane, known as the Reimer-Tiemann reaction, to provide disubstituted salicylaldehydes of general formula (27). An alternate set of reaction conditions involves reaction with magnesium methoxide and paraformaldehyde (Aldred, J. Chem. Soc. Perkin Trans. 1 (1994), 1823). 
An alternative method of preparing benzaldehydes of general formula (21), wherein R12 is selected from alkyl, haloalkyl, chlorine, fluorine, haloalkoxy, alkoxy, alkylthio, nitro, alkylcarbonyl, arylcarbonyl, xe2x80x94NR82R83, and xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R10 is selected from alkyl, hydroxyalkyl, alkylthio, alkylcarbonyl, and formyl, is described in Scheme 9. Protected benzaldehydes of general formula (29), wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred, can be converted to the 3,4-disubstituted benzaldehyde of general formula (23) via conversion of the bromide to an intermediate lithio or magnesio derivative, followed by reaction with an appropriate electrophile such as an aldehyde, dialkyldisulfide, a Weinreb amide, dimethylformamide, an alkyl halide or other electrophile followed by deprotection of the acetal to provide benzaldehydes of general formula (21). 
An alternative method of preparing benzaldehydes of general formula (21), wherein R10 is selected from alkyl, haloalkyl, chlorine, fluorine, haloalkoxy, alkoxy, alkylthio, xe2x80x94NR82R83, and xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R12 is selected from alkyl, hydroxyalkyl, alkylthio, alkylcarbonyl, arylcarbonyl, and formyl, can be used as described in Scheme 10. Protected benzaldehydes of general formula (31), wherein R is selected from alkyl or together with the oxygen atoms to which they are attached form a 5 or 6 membered ring wherein 1,3-dioxolanes are preferred can be processed as described in Scheme 9 to provide benzaldehydes of general formula (21). 
Benzaldehydes of general formula (33), wherein R10 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, xe2x80x94NR82R83, and xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R13 is selected from hydrogen, alkyl, arylalkyl, and haloalkyl wherein preferred haloalkyl groups are selected from difluoromethyl, 2,2,2-trifluoroethyl and bromodifluoromethyl, can be prepared as described in Scheme 11. 3-Hydroxybenzaldehyde of general formula (32) can be treated with suitable alkylating reagents such as benzylbromide, iodomethane, 2-iodo-1,1,1-trifluoroethane, chlorodifluoromethane, or dibromodifluoromethane in the presence of base such as potassium carbonate, potassium tert-butoxide or sodium tert-butoxide, to provide benzaldehydes of general formula (33). The synthesis of useful 3-hydroxybenzaldehydes of general formula (32) may be found in the following literature references: J. Chem. Soc. (1923), 2820; J. Med Chem. (1986), 29, 1982; Monatsh. Chem. (1963), 94, 1262; Justus Liebigs Ann. Chem. (1897), 294, 381; J. Chem. Soc. Perkin Trans. 1 (1990), 315; Tetrahedron Lett. (1990), 5495; J. Chem. Soc. Perkin Trans. 1 (1981), 2677. 
Benzaldehydes of general formula (35), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, xe2x80x94NR82R83, and xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R13 is selected from hydrogen, alkyl, arylalkyl, and haloalkyl wherein preferred haloalkyl groups are selected from difluoromethyl, 2,2,2-trifluoroethyl, and bromodifluoromethyl, can be prepared as described in Scheme 12. 4-Hydroxybenzaldehydes of general formula (34) can be treated with suitable alkylating reagents such as benzylbromide, iodomethane, 2-iodo-1,1,1-trifluoroethane, chlorodifluoromethane, or dibromodifluoromethane, in the presence of base such as potassium carbonate, potassium tert-butoxide or sodium tert-butoxide to provide benzaldehydes of general formula (35). The synthesis of useful 4-hydroxybenzaldehydes of general formula (34) may be found in the following literature references: Angyal, J. Chem. Soc. (1950), 2141; Ginsburg, J. Am. Chem. Soc. (1951), 73, 702; Claisen, Justus Liebigs Ann. Chem. (1913), 401, 107; Nagao, Tetrahedron Lett. (1980), 21, 4931; Ferguson, J. Am. Chem. Soc. (1950), 72, 4324; Barnes, J. Chem. Soc. (1950), 2824; Villagomez-Ibarra, Tetrahedron (1995), 51, 9285; Komiyama, J. Am. Chem. Soc. (1983), 105, 2018; DE 87255; Hodgson, J. Chem. Soc. (1929), 469; Hodgson, J. Chem. Soc. (1929), 1641. 
An alternate method for introduction of substituents at the 3-position of benzaldehydes of general formula (21), wherein R10 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NR82R83, wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl can be used as described in Scheme 13. This method, also known as the Sandmeyer reaction, involves converting 3-amino benzaldehydes of general formula (36) to an intermediate diazonium salt with sodium nitrite. The diazonium salts can be treated with a bromine or iodine source to provide the bromide or iodide. The Sandmeyer reaction and conditions for effecting the transformation are well known to those skilled in the art of organic chemistry. The types of R12 substituents that may be introduced in this fashion include cyano, hydroxy, or halo. In order to successfully carry out this transformation it may in certain circumstances be advantageous to perform the Sandmeyer reaction on a protected aldehyde. The resulting iodide or bromide can be treated with unsaturated halides, boronic acids or tin reagents in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) to provide benzaldehydes of general formula (21). The diazonium salts may also be treated directly with unsaturated halides, boronic acids or tin reagents in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) to provide benzaldehydes of general formula (21). 
An alternate method for introduction of substituents at the 4-position of benzaldehydes of general formula (21), wherein R12 is selected from hydrogen, alkyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, halo, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NR82R83, wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, can be used as described in Scheme 14. This method, also known as the Sandmeyer reaction, involves converting 4-amino benzaldehydes of general formula (37) to an intermediate diazonium salt with sodium nitrite and then treating the diazonium salts in a similar manner as that described in Scheme 13. The types of R10 substituents that may be introduced in this fashion include cyano, hydroxy, or halo. The Sandmeyer reaction and conditions for effecting the transformation are well known to those skilled in the art of organic chemistry. In order to successfully carry out this transformation it may in certain circumstances be advantageous to perform the Sandmeyer reaction on a protected aldehyde. 
4-Bromo-3-(trifluoromethoxy)benzaldehyde or 4-chloro-3-(trifluoromethoxy)benzaldehyde can be prepared as described in Scheme 15. The commercially available 4-bromo-2-(trifluoromethoxy)aniline can be protected on the amino group with a suitable N-protecting group well known to those skilled in the art of organic chemistry such as acetyl or tert-butoxycarbonyl. The bromine can then be converted to the lithio or magnesio derivative and reacted directly with dimethylformamide to provide the 4-aminoprotected-3-(trifluoromethoxy)benzaldehyde derivative. Removal of the N-protecting group followed by conversion of the amine to a bromide or chloride via the Sandmeyer method of Scheme 14 provides 4-bromo-3-(trifluoromethoxy)benzaldehyde or 4-chloro-3-(trifluoromethoxy)benzaldehyde. 
4-Trifluoromethylbenzaldehydes of general formula (39), wherein Y is selected from cyano, nitro, and halo may be prepared according to the method of Scheme 16. 4-Trifluoromethylbenzoic acid is first nitrated, using suitable conditions well known in the literature such as nitric acid with sulfuric acid, and the carboxylic acid group reduced with borane to provide 3-nitro-4-trifluoromethylbenzyl alcohol. From this benzyl alcohol may be obtained the 3-nitro-4-trifluoromethylbenzaldehyde by oxidation with typical reagents such as manganese dioxide. The nitro benzylic alcohol can be reduced to the aniline using any of a number of different conditions for effecting this transformation among which a preferred method is hydrogenation over a palladium catalyst. The aniline can be converted to either a halo or cyano substituent using the Sandmeyer reaction described in Scheme 13. Benzyl alcohols of general formula (38) can be oxidized using conditions well known to those skilled in the art such as manganese dioxide or swern conditions to provide benzaldehydes of general formula (39).
For certain aromatic ring substitutions of R1 for compounds of the present invention it is preferable to effect transformations of the aromatic ring substitutions after the aldehyde has been incorporated into the core structure of the present invention. As such, compounds of the present invention may be further transformed to other distinct compounds of the present invention. These transformations involve Stille, Suzuki and Heck coupling reactions all of which are well known to those skilled in the art of organic chemistry. Shown below are some representative methods of such transformations of compounds of the present invention to other compounds of the present invention. 
Dihydropyridines of general formula (42), wherein R8, R9, D, E, Q, V, X, m, and n are as defined in formula (I), R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, and alkylthio, and xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, R12 is selected from alkyl, vinyl, aryl, heteroaryl, cyano and the like, can be prepared as described in Scheme 17. Compounds of general formula (41), wherein Y is selected from bromine, iodine, and triflate, are protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be treated with a suitable tin, boronic acid, or unsaturated halide reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (42). The conditions for this transformation also effect the removal of the Boc protecting group. 
Dihydropyridines of general formula (44), wherein R8, R9, D, E, Q, V, X, m, and n are as defined in formula (I), R12 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, R10 is selected from alkyl, vinyl, aryl, heteroaryl, cyano and the like, can be prepared as described in Scheme 18. Dihydropyridines of general formula (43), wherein Y is selected from bromine, iodine, and triflate, can be protected with a tertbutoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be reacted with a suitable tin, boronic acid, or unsaturated halide reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (44). The conditions for this transformation also effect the removal of the Boc protecting group. 
Dihydropyridines of general formula (47), wherein R8, R9, D, E, Q, V, X, m, and n are as defined in formula (I), R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, alkylthio, and xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, and R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, can be prepared as described in Scheme 19. Dihydropyridines of general formula (41), wherein Y is selected from bromine, iodine, and triflate can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be treated with a suitable halozinc reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (47). The conditions for this transformation also effect the removal of the Boc protecting group. The types of meta substituents that may be introduced in this fashion include trihalopropenyl and more specifically the trifluoropropenyl group. 
Dihydropyridines of general formula (48), R8, R9, D, E, Q, V, X, m, and n are as defined in formula (I), R10 is selected from hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, heteroaryl, cyano, haloalkyl, chlorine, fluorine, haloalkoxy, nitro, alkoxy, alkylthio, xe2x80x94C(O)NR82R83 wherein R82 and R83 are independently selected from hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, and formyl, R11 is selected from hydrogen, hydroxy, alkoxy, haloalkoxy, and arylalkoxy, can be prepared as described in Scheme 20. Dihydropyridines of general formula (43), wherein Y is selected from bromine, iodine, and triflate can be protected with a tert-butoxycarbonyl (Boc) group using standard procedures. The aromatic bromide, iodide, or triflate can be treated with a suitable halozinc reagent in the presence of a palladium catalyst with heating in a solvent such as dimethylformamide to effect a coupling reaction that provides dihydropyridines of general formula (48). The conditions for this transformation also effect the removal of the Boc protecting group. The types of para substituents that may be introduced in this fashion include trihalopropenyl and more specifically the trifluoropropenyl group. 
Fused pyrimidines of general formula (52), wherein R1, X, Q, V, R8, D, E, m and n are as defined in formula (I) and R9 is selected from alkenyl, alkynyl, aryl and heterocycle, can be prepared according to the method of Scheme 21. Fused pyrimidines of general formula (50) may be treated with N-bromosuccinimide (NBS) in a solvent such as methylene chloride to provide bromides of general formula (51). Bromides of general formula (51) may be treated with a palladium (0) catalyst such as tetrakis(triphenylphosphine)palladium (0), an organoborane reagent and a base such as cesium fluoride or potassium carbonate under Suzuki conditions which are known to those of skill in the art (Syn. Comm. 11, 1981, 513; JOC 49, 1984, 5237; Tet. Lett. 26, 1985, 5997; Tet. Lett. 28, 1987, 5093; and Tet. Lett. 28, 1987, 5097) to provide fused pyrimidines of general formula (52). Bromides of general formula (51) may also be treated with a palladium (0) catalyst such as tetrakis(triphenylphosphine)palladium (0) and a tin reagent under Stille conditions which are known to those of skill in the art (JACS 101, 1979, 4992) to provide fused pyrimidines of general formula (52). Bromides of general formula (51) may also be treated with a palladium (0) catalyst, an aryl halide (Br or I) or a heterocyclic halide (Br or I) and a base such as triethylamine under binary coupling conditions or Heck conditions which are known to those of skill in the art to provide fused pyrimidines of general formula (52).